Durability and success capability of HAART: 4.5 years follow-up
Researchers from the Royal Free Hospital, London, looking into viral breakthrough after suppression with highly active antiretroviral therapy (HAART) studied the experience of 233 individuals with viral loads of less than 50 copies/ml followed for up to four years
Fiona Lamp and colleagues write: “…if initial viral suppression is achieved, and adherence to therapy can be maintained, the chance of treatment failure is extremely low.” In this study there was a total of 12 viral failures after three years on HAART. Patients were followed for 4.5 years and there were no viral failures after three years.
The occurrence of viral breakthrough on treatment was examined in 233 previously antiretroviral-naive HIV-infected patients who started HAART and who achieved initial viral suppression to less than 50 copies/ml. The rate of viral breakthrough despite the continuation of therapy was 3.6 per 100 person-years (12 cases occurred during 332.8 person-years of follow-up). Viral suppression on HAART is proving extremely durable in those who can tolerate these regimens over long periods.
It is known that current HAART regimens initially reduce the viral load to less than 50 copies/ml in the majority of drug-naive individuals within 24-32 weeks. Whether current regimens have the potential to sustain this level of viral suppression indefinitely is uncertain. Drug toxicity and the complexity and inconvenience of treatment schedules present major obstacles to the continuous, long-term use of HAART. A key question, however, is whether HAART regimens would have sufficient sustained intrinsic efficacy, even if it were possible to maintain good adherence indefinitely. A recent report from the Frankfurt clinic cohort found that viral rebound (occurring after viral suppression to less than 50 copies/ml with HAART) was associated with complete treatment interruption in the vast majority of cases, leaving few cases that could be attributed to genuine treatment failure. Researchers investigated the occurrence of viral breakthrough despite the continuation of therapy among patients from the Royal Free Hospital HIV clinic, who had achieved initial viral suppression with HAART.
The rate of viral breakthrough on treatment was assessed in all 233 patients who fulfilled the following three criteria: (1) they were naive to antiretroviral drugs when they started a three-drug HAART regimen (either three nucleoside inhibitors including abacavir, or two nucleoside inhibitors plus one non-nucleoside reverse transcriptase inhibitor, or two nucleoside inhibitors plus a protease inhibitor (PI), including ritonavir-boosted PI), (2) they reached a viral load of less than 400 copies/ml within 32 weeks of starting HAART; and (3) they also reached a viral load of less than 50 copies/ml without having previously interrupted treatment or experienced viral breakthrough. Both (2) and (3) were necessary as the lower limit of quantification of viral load (using the Roche reverse transcriptase-polymerase chain reaction-based approach; Roche Molecular Systems, Welwyn Garden City, UK) was 400 copies/ml from 1996 to 1998, and has been 50 copies/ml only from 1998 onwards.
Viral breakthrough on treatment was defined as either the first of two consecutive values greater than 400 copies/ml, or a value greater than 50 copies/ml that was followed by the initiation of at least two new drugs. If all antiretroviral drugs were stopped after viral suppression to less than 50 copies/ml, the follow-up time was right-censored at that point and simultaneous or subsequent viral rebounds were not counted. Therefore, the follow-up time for each individual was defined as the time from a viral load of less than 50 copies/ml to the first of: viral breakthrough, stopping all drugs, or the final viral load measurement.
Twenty-one per cent of subjects were female; the main HIV exposures were homosexual (60%) and heterosexual (34%) sex. HAART was started at a median age of 35 years and on a median date of December 1998 (range September 1996-November 2000). Baseline median (interquartile range; IQR) viral loads and CD4 cell counts were 5.3 (4.8-5.7) log copies/ml and 194 (76-302) cells/mm3, respectively. Nucleoside combinations in the initial regimen were zidovudine/lamivudine 125 (54%), stavudine/lamivudine 74 (32%) and other 34 (14%). Other drugs were nevirapine 57 (24%), efavirenz 44 (19%), nelfinavir 49 (21%), indinavir 32 (14%), ritonavir 21 (9%), ritonavir-boosted protease inhibitor 27 (12%), and abacavir three (1%).
The median (IQR) weeks from the start of HAART to the first measured values of 400 copies/ml and 50 copies/ml were 10.1 (7.4, 15.9) and 26.1 (17.9, 42.4), respectively. Overall, there were 1,277 viral load measures made over a total of 332.8 person-years of follow-up after the first viral load of less than 50 copies/ml, an average of one measure per 13.5 weeks per patient. The maximum follow-up times were 4.5 years from the start of HAART and four years from the first viral load of less than 50 copies/ml. Overall, only 12 individuals (5.2%) experienced viral breakthrough on therapy (11 according to the first failure criterion and one according to the second criterion). Therefore, the rate of viral breakthrough on treatment was 3.6 per 100 person-years, equivalent to one individual with viral breakthrough per 27.8 person-years of follow-up.
Researchers examined the records of the 12 patients who had experienced viral breakthrough, and found that eight had subsequently had a resistance test. Results were available for six of these; major resistance mutations were present in five of the six. Information on adherence was available for six of the 12 patients; adherence difficulties were noted in three. These three did not include any of the five patients in whom major resistance was detected.
The low rate of viral breakthrough on treatment observed in this study confirms the results of a similar analysis based on the Frankfurt clinic cohort. This suggests that if initial viral suppression is achieved, and adherence to therapy can be maintained, the chance of treatment failure is extremely low. Other studies have indicated that non-adherence may be the most important reason for the initial lack of response to HAART and subsequent viral rebound. In this study, the intention was to count only viral breakthrough on treatment. However, it seems that lack of adherence may have been associated with at least some of the cases of viral breakthrough.
Drug resistance appeared to be a major explanatory factor, but whether this in itself was caused by adherence difficulties in some patients is unclear. If some of the cases of viral breakthrough were related to adherence, the true intrinsic treatment failure rate would be even lower. In the Frankfurt study, the rate of viral breakthrough decreased as the time since starting HAART increased. In the present analysis there was no significant change over time in the rate of breakthrough, although no cases occurred after three years. If the rate of 0.036 per person-year that these researchers observed were to continue indefinitely, the median time before an individual experienced viral breakthrough would be approximately 20 years.
Whether sustained adherence to treatment over such long periods will be achievable with the drugs that are currently available is extremely doubtful. The development of drug regimens that overcome some of the current problems of toxicity and inconvenience would therefore be a major advance in enabling the successful long-term treatment of HIV. In conclusion, viral suppression on HAART is proving extremely durable in those who can tolerate these regimens over long periods.
Lampe FC; Johnson MA; Lipman M et al. Viral breakthrough after suppression with highly active antiretroviral therapy: experience from 233 individuals with viral loads of less than 50 copies/ml followed for up to four years. AIDS 2003; 17(5):768-770.
This highlights the importance of the first weeks and months of therapy for all critical aspects of ARV treatment – for treatment choice, monitoring, adherence, resistance, side effect management and, probably therapeutic drug levels. Investment of resources to achieve this initial viral suppression will be repaid with long-term treatment success. Many patients still do not understand the critical nature of these first weeks of therapy.
It also emphasises that continual attention to adherence is necessary to guard against adherence fatigue which may set in after years of pill swallowing as well as the obvious need for the development of non-toxic regimens.